Spirocycles of general structural Formula I: ##STR2## where R.sub.1 is selected from the group consisting of acyl such as CO--C.sub.1-3 alkyl, cyano, carboxy, carboxy C.sub.1-6 alkyl ester, carboxamide, C.sub.1-6 alkyl sulfinyl, C.sub.1-6 alkyl sulfonyl, C.sub.1-6 methanesulfonamide and halogen; R.sub.2 is selected from the group consisting of keto or alcohol, R.sub.3 is cyano, are compounds which are Class III antiarrhythmic agents.
Antiarrythmic agents of Class III are drugs which cause a selective prolongation of the duration of the action potential without a significant depression of the V.sub.max. Drugs in this class are limited. Examples such as sotalol and amiodarone have been shown to possess Class III properties. Sotalol also possesses Class II effects which may cause cardiac depression and be contraindicated in certain susceptible patients. Also, amiodarone is severely limited by side effects. Drugs of this class are expected to be effective in preventing ventricular fibrillation. Pure Class III agents, by definition, are not considered to cause myocardial depression or an induction of arrhythmia due to the inhibition of the action potential conduction as seen with Class I antiarrhythmic agents.
A number of antiarrhythmic agents have been reported in the literature, such as those disclosed in:
(1) EP 397,121-A, PA1 (2) EP 300,908-A, PA1 (3) EP 307,121, PA1 (4) U.S. Pat. No. 4,629,739, PA1 (5) U.S. Pat. No. 4,544,654, PA1 (6) U.S. Pat. No. 4,788,196, PA1 (7) EP application 88302597.5, PA1 (8) EP application 88302598.3, PA1 (9) EP application 88302270.9, PA1 (10) EP application 88302600.7, PA1 (11) EP application 88302599.1, PA1 (12) EP application 88300962.3, PA1 (13) EP application 235,752, PA1 (14) DE 3633977-A1, PA1 (15) U.S. Pat. No. 4,804,662, PA1 (16) U.S. Pat. No. 4,797,401, PA1 (17) U.S. Pat. No. 4,806,555, PA1 (18) U.S. Pat. No. 4,806,536.
Compounds of similar structure are found in Japanese patent publication 88-63533-B of Daiichi Pharmaceutical Co.; J. Med. Chem., 19, 1315 (1976) by Bauer et al.; Iorio et al. in II. Farmaco-Ed Sci., 32, 212-219 (1977): Houlihan et at., U.S. Pat. No. 3,686,186; Davis et at., U.S. Pat. No. 4,420,485; Kealey, U.S. Pat. No. 4,810,792; Parham et al., J. Org. Chem., 41, 2629 (1976). None of the compounds disclosed in the foregoing references are alleged to have antiarrhythmic activity.